Mark Cucuzzella
West Virginia University School of Medicine
WVU Center for Diabetes and Metabolic Health, Morgantown, West VirginiaE-mail:[email protected]

Abstract

Type 2 diabetes (T2DM) is most often treated as a chronic progressive condition. However, both clinical experience and scientific studies have shown that remission indicated by a normalizing of blood glucose levels and safe medication reduction through lifestyle change should be considered an achievable clinical outcome for patients with T2DM. Dietary interventions that include therapeutic levels of carbohydrate reduction can be used by clinicians to help patients reach this goal, as evidenced by clinical experience and clinical trials; however, many clinicians and allied healthcare providers have not been trained in how to administer these therapies. This article demonstrates the successful implementation of therapeutic carbohydrate reduction for T2DM in an inpatient setting through the institutional example of a small, rural hospital in the U.S. It provides definitions for therapeutic carbohydrate reduction and a rationale for its use in an inpatient setting in patients who present with T2DM. The article outlines a seven-stage protocol developed from practice-based evidence to be used in an inpatient setting to minimize the requirement for insulin or other hypoglycemic medications and to normalize markers of T2DM in patients with this condition. The protocol consists of: 1) patient selection; 2) pre-diet evaluation and counseling; 3) patient education; 4) initiating the dietary intervention; 5) managing medication changes; 6) addressing any side effects; and 7) follow-up. This protocol serves as an initial framework for developing clinical practice guidelines and a standard of care for using carbohydrate reduction as an intervention for T2DM and related conditions in an inpatient setting. It also indicates the potential for providing clinicians with the opportunity to help patients put T2DM into remission, rather than just manage its progression. A Clinician’s Guide to Inpatient Low-Carbohydrate Diets for Remission of Type 2 Diabetes: Toward a Standard of Care Protocol.

Keywords

diabetes,
glycemic,
insulin

Introduction

Type 2 diabetes mellitus (T2DM) is now
considered a global pandemic. Recent estimates
from the World Health Organization indicate
over 400 million people worldwide have diabetes
[1]. In the United States, at least 23 million
people have been diagnosed with diabetes,
and it is estimated that nearly 50% of the US population may be classified as having preor
undiagnosed diabetes [2,3]. T2DM is a
leading cause of morbidity and mortality and
is a significant factor in increasing healthcare
costs due to its extensive complications. The
American Diabetes Association estimates the
annual costs associated with T2DM to be over
$300 billion in 2017 [4]. In January 2017, the
American Diabetes Association and American Academy of Family Physicians labeled T2DM as
a chronic progressive disease [5]. However, both
clinical experience and scientific studies have
shown that bringing progression to a standstill
and even reversing the clinical manifestations
of T2DM should be considered an achievable
clinical outcome. Currently in the literature
there are four methods to place T2DM into
remission: bariatric surgery [6], extended
fasting [7], a very low-calorie diet using a mealreplacement
formula [8], and low-carbohydrate
diets [9,10]. Low-fat, plant-based protocols have
been suggested as first line therapy for diabetes
management, but the most intensive protocol
failed to achieve remission of T2DM over 74
weeks, as hemoglobin A1c (HbA1c) reduction
was 8.1 to 7.6 [11]. Low-carbohydrate diets
are therapeutic interventions that clinicians can
use to help patients discontinue medications for
hyperglycemia and achieve remission of T2DM
[9,10]. For patients, this approach may be less
extreme, safer, and more acceptable than bariatric
surgery, extended fasting, and a very low-calorie
meal replacement. At the same time, lowcarbohydrate
dietary interventions are not clearly
defined in the literature, and many clinicians and
allied healthcare providers have not been trained
in how to administer these therapies. This article
serves as an initial framework for developing
clinical practice guidelines and a standard of
care for using carbohydrate reduction as an
intervention for T2DM and related conditions
in an inpatient setting. Dietary modification
in the form of carbohydrate restriction was a
primary form of diabetes care before the advent
of insulin therapy [12]. The use of exogenous
insulin revolutionized the care of type 1 diabetes
and also became established as a therapy in
T2DM, despite the differences in underlying
pathophysiology. The ubiquitous use of insulin
and other pharmacologic strategies to reduce
glycemia overtook the low-carbohydrate diet as
a standard treatment of T2DM. This shift was
accentuated by the U.S. Dietary Guidelines
emphasis on dietary fat restriction with a
concurrent emphasis on increasing the proportion
of dietary carbohydrate. However, there has been
increased interest in the therapeutic potential
for carbohydrate reduction for the treatment
of metabolic disease over the past 10 years.
Although it is well-accepted that close glycemic
control is an important factor for preventing
microvascular complications such as neuropathy
and retinopathy, modern treatment of T2DM
using pharmacological approaches does not consistently normalize HbA1c and has not
been shown to consistently slow the progression
of patients towards diabetic complications,
morbidity, and mortality [13]. Furthermore,
recent studies have suggested that reliance on
more intensive treatment may be detrimental.
The Action to Control Cardiovascular Risk in
Diabetes (ACCORD) trial, which compared
intensive versus standard insulin and medical
therapy, shows that intensive medical treatment
carries an increased risk of all-cause mortality, a
35% increased risk of cardiovascular mortality,
and a greater risk of hypoglycemic events and
weight gain of 10 kg in comparison to those
on standard therapy [14]. Other multinational,
multicenter, randomized controlled trials aimed
at achieving tight blood glucose control with
medications failed to demonstrate the expected
reductions in heart disease, the primary cause of
mortality in patients with diabetes, or in overall
mortality [15-20]. In contrast to these outcomes,
strong evidence exists for a promising alternative
approach. The recent literature regarding
the risks and benefits of intensive glycemic
management of T2DM have influenced the
relaxation of the HbA1c targets in the American
College of Physicians guidance statement
[21]. This reflects the current uncertainty
regarding the prioritization of glycemic control
in the pathophysiology of T2DM. Dietary
approaches to improve glycemic control through
carbohydrate reduction are often overlooked as a
safe, effective means to normalize HbA1c levels
without escalating medication therapy and the
risk of hypoglycemia and other adverse events.
A low-carbohydrate diet can be a useful tool for
clinicians to safely achieve clinical improvement,
but challenges to implementation in a clinical
context remain. Confusion about different
types of carbohydrate restriction, unfamiliarity
with the dietary intervention, concerns about
overmedication, time constraints, institutional
inertia, and limited resources all present
significant barriers to implementation of a lowcarbohydrate
diet in a clinical setting. This article
provides a case study of one hospital’s use of lowcarbohydrate
diets as a therapeutic intervention
in an inpatient setting. The article defines the
various levels of carbohydrate reduction, describes
the therapeutic potential for low-carbohydrate
dietary interventions for T2DM, and discusses
how to this therapy may be used in an inpatient
setting with transition to outpatient care. By
outlining a clinical protocol and providing
resources for the implementation of a therapeutic low-carbohydrate dietary intervention, some
barriers to using this intervention as an inpatient
intervention for the treatment of T2DM and
related conditions may be reduced.

Defining carbohydrate reduction

Dietary carbohydrate reduction can take many
forms. More precise definitions for the variety
of therapeutic approaches that carbohydrate
reduction represents are needed. The following
levels of carbohydrate reduction are based on
protocols currently in use and on definitions
found in the literature: VLCK (very lowcarbohydrate
ketogenic) diets recommend 30
g or less of dietary carbohydrate per day [10].
Restriction of kilocalorie (kcal) is not typically
recommended. LCK (low-carbohydrate
ketogenic) diets recommend 30-50 g of dietary
carbohydrate per day [22]. Sometimes “net
carbs” (calculated by total carbohydrate minus
fiber) will be used with a goal of 25-30 g net
carbs/day. Restriction of kcals is not typically
recommended. RC (reduced-carbohydrate) diets
recommend at least 50 g, but less than 130 g of
dietary carbohydrate per day, a level that is higher
than therapeutic levels listed above and lower than
the U.S. Institute of Medicine dietary reference
intake (DRI) for carbohydrate [23]. Restriction
of kcals may or may not be recommended at this
level. MCCR (moderate-carbohydrate, calorierestricted)
diets recommend more than 130 g
of dietary carbohydrate per day with a range of
45-65% of daily kcals coming from carbohydrate
[22]. In most cases, kcals are also restricted to
maintain energy balance or to achieve a deficient
for weight loss. This dietary intervention reflects
the amount of dietary carbohydrate typically
found in the “carbohydrate counting” dietary
intervention that is given to many people with
T2DM. Although this article follows common
practice in using the term “low-carbohydrate diet”
to refer to a variety of carbohydrate-reduction
therapies implemented in clinical settings that
fall below 130 g of dietary carbohydrate per
day, the specific protocol under discussion here
is a LCK diet. Clinicians should note that other
interventions for remission of T2DM, such as
very low-calorie diets or intermittent fasting,
effectively reduce carbohydrate intake as part
of overall kcal reduction. Conversely, reducing
carbohydrate intake in practice often serves to
reduce overall kcal. Recommendations for kcal
restriction or “calorie counting” are not typically
part of VLCK and LCK clinical interventions,
but may be used in research protocols.

Therapeutic potential in T2DM

The pathogenesis of T2DM is of progressive
insulin resistance to which the body responds
with increased insulin secretion. Consequent
hyperinsulinemia drives glucose and free fatty
acids to be stored in adipose tissue, muscle,
and visceral organs, which results in continued
weight gain, worsening insulin resistance, and
dependence on higher circulating insulin levels.
Chronic hyperinsulinemia may lead to beta-cell
exhaustion and failure of insulin production.
Insulin acts as a proliferative signaling molecule
and hyperinsulinemia may contribute to the
development of cardiovascular and inflammatory
disease [24,25]. The hyperglycemia of T2DM
occurs when systemic insulin resistance
overwhelms the ability of the pancreas to
produce an adequate amount of insulin. A lowcarbohydrate
diet limits foods containing starch
or sugar to minimize blood glucose excursions
and subsequent insulin demands. Thus the basic
mechanism of a low-carbohydrate diet aims to
interrupt the disease progression by maintaining
normoglycemia while reducing insulin demand
and reducing insulin resistance over time.
Low-carbohydrate diets typically minimize the
requirement for insulin or other hypoglycemic
medications. In contrast to pharmacological
methods, a low-carbohydrate diet carries lower
risk of hypoglycemia and ameliorates the need for
progressive increases in pharmacologic therapy.
A recent comparison of a LCK diet against a
MCCR diet showed greater weight loss and
better glycemic control in those following the
LCK, at both 6 and 12 months of study [22]. In
the aforementioned study, the metabolic benefits
were followed by the removal of anti-diabetic
medications in the LCK group, but not in the
MCCR group. The amelioration of metabolic
derangement and reduction of dependency upon
insulin or other hypoglycemic medications in a
number of clinical trials suggests that diabetes is,
for some, a reversible condition [10,26-30].

Inpatient protocol

The protocols and resources presented here
were discussed and edited by a collaboration of
physicians and allied health care providers who
have experience with utilizing low-carbohydrate
therapies in their practices. The pathway for
remission of T2DM through the use of a LCK
dietary intervention has been used for 3 years
at Jefferson Medical Center in West Virginia,
a 24-bed critical access hospital affiliated with
West Virginia University (WVU). This small rural hospital serves a county with a population
under 100,000 whose health demographics
are representative of the state with the highest
obesity and diabetes rates in the U.S. This
institutional example demonstrates the successful
implementation of therapeutic carbohydrate
reduction for T2DM in an inpatient setting. The
inpatient setting provides a unique opportunity
to implement a low-carbohydrate approach,
although it also includes several challenges for the
clinician. An inpatient setting allows a carefully
controlled environment in which to change the
diet, measure response, and titrate medications
appropriately. Through inpatient initiation
of therapeutic carbohydrate reduction, a new
medication regimen can safely be established
before discharge with plans for outpatient
follow-up. Specifically, short-acting meal time
insulin dosages can usually be discontinued or
dramatically decreased, which also serves as a
teaching tool for patients regarding effects of
dietary carbohydrate on medication use. The
disruption of an inpatient hospitalization can
also inspire motivation for long-term behavior
change. Furthermore, the inpatient setting
benefits from more time to coordinate education
and follow-up. Ideally, a multi-disciplinary team
approach that includes the hospital provider,
pharmacy, nursing, dietary and nutrition services
will be appropriately trained and available
to collaborate on the implementation of this
intervention. This multidisciplinary team can
assist in medication management and patient
education. Mobilizing an interdisciplinary team
approach for education, clinical management
and follow-up has been successfully modeled in
the community hospital setting described above.
Despite these advantages, there are significant
logistical and institutional barriers to widespread
use of therapeutic carbohydrate reduction for
T2DM in an inpatient setting. First, eligible
patients are limited due to the acute nature of
short-stay inpatient admissions and tension
between addressing acute versus chronic health
concerns. Additionally, time and financial costs
needed for educating food service staff and
administering the diet can be prohibitive in many
institutions. Finally, defying recommendations
for fat- or salt-restricted diets represents an
additional regulatory challenge. Many patients
are placed on salt- or fat-restricted diets, which
contradict the dietary pattern recommended
for T2DM remission in this protocol. These
challenges require a level of active engagement
and critical thinking by the clinician and team. For example, a patient with T2DM, hypertension
(HTN), and coronary artery disease (CAD)
would typically be placed on a salt- and fatrestricted
diet as part of usual care. However, if it
seems likely that T2DM is at the root of both of
the CAD and HTN, the clinician would need to
prioritize the dietary pattern supporting T2DM
remission. Appendix 1 (“Clinician’s Guide to
Low-Carb Diets”) provides a clinician-oriented
overview that describes how and why a LCK
dietary intervention may be used as a therapy for
T2DM. This pamphlet may be used to initiate
discussions in hospitals or clinical settings with
regard to increasing the opportunities for patients
to have the option to reverse T2DM using a lowcarbohydrate
dietary approach. We describe a
seven-stage protocol for implementing a LCK
diet in an inpatient setting. This protocol has been
successfully used to minimize the requirement
for insulin or other hypoglycemic medications
and to normalize markers of T2DM. This
indicates the potential for providing clinicians
with the opportunity to help patients reverse
T2DM, rather than just manage its progression.
The seven-stage protocol consists of: 1) patient
selection; 2) pre-diet evaluation and counseling;
3) patient education; 4) initiating the dietary
intervention; 5) managing medication changes;
6) addressing any side effects; and 7) followup.
It should be noted that similar methods for
treating T2DM with a low-carbohydrate dietary
intervention have been implemented globally
in a variety of settings. The authors are familiar
with the clinical application of low-carbohydrate
diets in multiple primary care practices in the
U.S., U.K., and Canada. Furthermore, the value
of reducing carbohydrate load in the diets of
those with T2DM has been recognized for over a
decade, and numerous clinical trials, case reviews,
and reports of clinical interventions using
therapeutic carbohydrate reduction exist [10,26-34]. However, documentation of protocols
indicating how clinicians may implement lowcarbohydrate
diets in hospital or outpatient
settings to treat T2DM and related conditions is
underrepresented in the medical literature.

Patient selection

The clinical approach described in this
document focuses on adults with prediabetes
(HbA1c 5.7-6.5%) and T2DM (HbA1c over
6.5%). These populations were selected due to
the strength of evidence base for utilization of
a low-carbohydrate diet as therapy, the health
burden of the disease, and the potential clinical
challenges to implementation as outpatients.

These patients must be able and prepared to:

•Use a blood glucometer to check serum
glucose if on insulin or insulin secretagogues
(sulfonylureas and meglitinides),

•Communicate with the health care team during
the LCK diet intervention

These guidelines will not extend to:

•Patients presenting with an acute, unstable
medical condition.

•Pregnant women or those breastfeeding.

•Pediatric patients.

Pre-diet evaluation and counseling

The evaluation and counseling of a patient
prior to initiation of a LCK diet can occur in
either an inpatient or outpatient setting. Initial
intake should include evaluation of patient’s
current symptoms, past medical history,
comorbidities, current medications, and baseline
laboratory workup. Pertinent components of
the past medical history include date of diabetes
diagnosis, time of progression to insulinrequirement
(if relevant), diabetes medication
history, history of hypoglycemic episodes, and
diabetes complications and co-morbidities.
Additional history should include polyuria and
dehydration. Special attention should be given
to the symptoms and timing of diagnosis and
insulin requirement to elucidate any component
of latent autoimmune diabetes in adults
(LADA) or maturity onset diabetes of the young
(MODY).

A basic laboratory workup should be completed
to rule out acute pathology and establish baseline
metrics. Initial laboratory tests should include
the following:

•Additional tests may include: Vitamin D,
C-peptide, uric acid, high-sensitivity C-reactive
protein (hsCRP), advanced lipid panel, fasting
insulin and homeostatic model of insulin resistance (HOMA-IR), glucose tolerance testing
(GTT). Clinicians should note that GTT can
be inaccurate if the patient is already on a LCK
diet. A patient’s readiness to change and support
are essential for proper initiation of this therapy.
The attending physician should share knowledge
and information on using a LCK dietary
intervention for T2DM as an option to usual
care. An exploration of the patient’s motivations,
psychosocial, and financial situation can give
insight into the patient’s behaviors and barriers
(e.g. disability, employment, and relationships)
to the success of this dietary and behavior
change intervention. In particular, capacity to
buy foods and prepare meals appropriate to the
intervention should also be determined. Initial
counseling may be done by any trained and
qualified member of the healthcare team. If a
patient chooses this intervention, the patient’s
care team—including pharmacy, nursing, and
dietary/nutrition—should be alerted in order
to align patient care in a way that will help the
patient be successful with this intervention.

Patient education

Adherence, satiety, and simplicity are critical to
early success. Appendix 2 (“Getting Started on
a Low-Carbohydrate Diet”) provides a brochure
that can be used to educate patients in how to
begin a LCK diet. Additionally, free resources
for clinicians to use in for patient education
can be found at many online sites, such as
DietDoctor.com. The entire healthcare team
should be familiar with the general principles of
how to reduce dietary carbohydrate as therapy
for T2DM so that information given the patient
is clear and consistent. The appropriate level of
carbohydrate reduction to meet therapeutic goals
will differ among patients; however, an amount
of less than 50 g of carbohydrate per day will
put most adults into nutritional ketosis. During
this state, the body relies primarily on fatty acids
and a small amount of ketones can be detected
in blood, urine or breath. Importantly, this
differs from ketoacidosis, in which an absolute
lack of insulin causes uncontrolled lipolysis
and large amounts of ketones cause metabolic
acidosis. Ketones may be measured, but we do
not advise this for the majority of our patients
due to cost and added complexity. However, if
patients understand the use of urine strips or a
breath or serum meter and wish to use them, we
do not discourage this. Measurement of urine
ketones can be helpful in the initiation phase of
this therapy. A less restrictive low-carbohydrate
intervention also has therapeutic potential even if it does not lead to a state of ketosis. A LCK
diet emphasizes whole food sources of protein
and fat, low-starch vegetables, full-fat dairy,
nuts, and seeds. Although this intervention
can be done as a vegetarian diet, the diet allows
animal products and seafood to be consumed to
satiety. In counseling, the emphasis should be
on foods and general carbohydrate restriction,
rather than monitoring macronutrient content.
Adequate protein and fat intake at each meal to
give a sense of satiety and satisfaction should be
emphasized. Most authorities agree on about 0.8
-1.0 grams of protein per kilogram of lean body
weight, but this can vary based on individual
needs and energy expenditure. Examples of
low-carbohydrate sources of protein and fat are
meat, fish, poultry, and non-meat sources such
as eggs, full-fat dairy, and low-carbohydrate nuts
(such as pecans and macadamias). A LCK diet
encourages the liberal inclusion of non-starchy
vegetables, particularly leafy greens, and sources
of natural plant fats such as avocados and olives.
Fiber from a variety of plant sources is thought
to be beneficial for the gut microbiome, but
this emerging area of interest is beyond the
scope of this paper [35,36]. A LCK diet allows
intake of natural fats to satiety. These include
any non-trans fats, such as olive oil, coconut oil,
avocado oil, full-fat dairy, and butter, along with
the fats naturally associated with whole food
protein sources. As it has not been determined
that saturated fats in foods contribute to
adverse health outcomes, foods thought to be
sources of saturated fat are not restricted for
this intervention [37]. Carbohydrate restriction
strongly limits the intake of grains (rice, wheat,
corn, oats) and grain-based products (cereals,
bread, biscuits, oatmeal, pastas, crackers),
starchy vegetables (potatoes, corn, legumes),
sweetened dairy products (fruit yogurts, flavored
milk products), sweetened desserts (gelatins,
puddings, cakes), and most fruits. In general,
fruit cannot be accommodated within the daily
carbohydrate intake, however, unsweetened
berries may be included in limited amounts. We
recommend non-starchy vegetables instead as
sources of fiber and micronutrients.

Initiating dietary intervention

The patient’s dietary order, as an inpatient
in the hospital, should be changed to limit
carbohydrate intake to 10 g per meal. To increase
adherence and reduce perceived hunger, the
dietary order may also include instructions to
“double eggs, meat, fish, salad and eliminate all
sugar/starch and sweet drinks.” This may require some education for the hospital food service.
Importantly, for hospitalized patients, this is not
a weight loss or calorie-restricted diet; it is a diet
for approaching normoglycemia and reducing
medication requirements for controlling blood
glucose. In most cases, sodium should not
be restricted because natriuresis occurs with
carbohydrate restriction. Many patients will
experience lower blood pressure within several
days of initiation of the diet, and some will
experience this immediately. In this setting,
post-meal blood glucose testing can serve as
an educational opportunity to demonstrate to
patients that if they do not eat carbohydratedense
foods such as sugars and starches, their
blood glucose does not go up with meals, even
without the administration of insulin.

Medication management

See Appendix 3 for an overview of medication
reduction guidelines for following patients with
T2DM on a LCK dietary. This table demonstrates
the alterations of medications that will be
necessary during the treatment of T2DM with a
LCK diet. As the diet continues to reduce blood
glucose and insulin resistance, hypoglycemic
medication must be carefully monitored and
titrated to prevent hypoglycemia. No “sliding
scale” insulin is needed to cover meals as patients
will not be consuming significant amount of
carbohydrate foods at mealtime. Short-acting
insulin may be needed to correct blood glucose
excursions over 200 mg/dL and bring them
down to 150 mg/dL range. The immediate goal
is not normoglycemia, but to wean patients off
of insulin or other hypoglycemic medications.
In this context, short term mild hyperglycemia
is safer than hypoglycemia. For patients with
T2DM who have some remaining beta cell
function, the healthcare team should consider
changing long-acting insulin to morning-only
glargine (Lantus), detemir (Levemir), or NPH
insulin; note none of these are 24-hour insulins.
Morning dosing fits better with normal circadian
and meal patterns and allows reduced insulin
load at night. This dose should be reduced to no
more than 40 units even if the patient is on highdose,
long-acting insulin at home. Patients with
beta cell failure will need a split dose of longacting
insulin. Patients may be weaned from
long-acting insulin and have it discontinued
entirely if blood glucose levels are consistently
low; hypoglycemia is rare with low-dose, longacting
insulin in the morning. Sulfonylureas and
insulin secretagogues should be discontinued
immediately, as directed in Appendix 3. SGLT2 inhibitors pose a risk for euglycemic acidosis and
therefore should be discontinued. The healthcare
team may consider adding an insulin-sensitizing
agent (metformin) if the patient is not already
taking this. This is contraindicated if eGFR is <30
ml/min, but in the impaired range of the kidneys’
estimated glomerular filtration rate (eGFR)
30-45 ml/min, a discussion of risk and benefit
should occur. Blood pressure often improves on
LCK diets. Symptoms of orthostasis, systolic
blood pressure below 120, or diastolic blood
pressure below 70 is an indication to wean patient
from antihypertensive medication. Diuretics are
problematic as carbohydrate reduction induces
naturesis. The healthcare team should consider
tapering these immediately unless indicated
for symptomatic heart failure. Renal protective
angiotensin-converting-enzyme (ACE)
inhibitors or angiotensin II receptor blockers
(ARBs) should be continued if proteinuria is
present, unless patient develops hypotensive
even on low dose. Patients should also be taught
home monitoring of blood pressure, so that
medication can be adjusted daily. When making
any significant dietary change, the healthcare
team should closely monitor drugs with a
narrow therapeutic window, such as some seizure
medications, digoxin, or antibiotics.

Adverse effects and supplementation

The most significant adverse effects from a
LCK diet originate from over-medication with
hypoglycemic and anti-hypertensive medications
following a dramatic dietary change. See
Appendix 3 for how to safely reduce medications
when a LCK diet is initiated. The insulinlowering
effects of a LCK diet can reduce the
resorption of sodium and other electrolytes in
the kidney. Sustained loss of salt via the urine
can contribute to hypovolemia and feelings
of fatigue and lethargy that some patients
experience when transitioning to a LCK diet.
It is recommended that patients on a LCK diet
consume normal amounts of salt, around 4-6g
per day [38]. Bouillon may be ordered for the
patient for this purpose, but it should not be
“low-sodium.” Further supplementation with
magnesium may also be helpful for patients
and should be considered on an individualized
basis (See Appendix 1 for more details). Good
hydration with water is essential, most often
over 2 liters a day. Some historical examples of
low-carbohydrate diets have greatly restricted the
intake of a variety of foods, and supplementation
with a multivitamin is often suggested in those
cases. The LCK diet for T2DM treatment described here emphasizes a wide variety of plant
and animal foods with high nutrient density. This
diet will provide adequate essential nutrition for
the majority of individuals; the recommendation
of multivitamin supplementation should be on
a personalized basis for the patient and is left to
the clinician’s and patient’s discretion. Individual
testing of Vitamin D, B12, folate, and magnesium
can guide supplementation. Supplements
containing medium chain triglycerides (MCT)
are often a part of ketogenic diets for neurological
treatments such as epilepsy. The MCTs contained
in these supplements are readily absorbed by
the liver and converted into ketone bodies.
Supplementation of MCT is not recommended
for the treatment of T2DM. Whereas the goal
of MCT supplementation with ketogenic diets
for epilepsy is to create high levels of ketones for
therapy, high levels of ketones are not necessary
for dietary treatment of T2DM. See Appendix
1 for additional information about treating side
effects that may occur during the transition to
a LCK diet. Although not a contraindication
to a LCK diet intervention, history of bariatric
surgery or cholecystectomy may require
individual tailoring based on diet tolerance. For
patients with previous cholecystectomy, dietary
fat will have to be increased gradually with
possible bile salt supplementation for persistent
gastrointestinal distress. History of gout or
elevated uric acid is not a contraindication to
the diet. Clinical experience has demonstrated
that adherence to a LCK diet may decrease
uric acid levels over time [35]. Initiation of the
diet may precipitate a flare but will likely result
in long-term improvement. Because a LCK
diet often involves changes in consumption of
Vitamin K-containing vegetables, monitoring of
International Normalized Ratio (INR) should be
more frequent in patients taking warfarin.

Discharge and follow-up

Prior to discharge, the healthcare team
should review medication changes and home
monitoring of blood glucose and blood pressure
if on medications. Patients should be educated in
a safe medication reduction strategy and should
have immediate access to an appropriately
trained healthcare provider for any questions or
concerns. Although resources may vary according
to clinic or hospital staff, contact email and cell
phone numbers should be available to patients.
To avoid confusion, electronically generated
discharge forms which might contradict the LCK
intervention should not be used. For example if
a patient has a diagnosis of T2DM, the standard hospital instructions often recommend 60 g carbs
per meal with 15 g carb snacks. Printed discharge
instructions for hypertension and heart failure
often advise salt reduction to less than 2 g per
day. These instructions are not appropriate for
patients following a LCK diet. Patients should
also be empowered to take charge of their health
with the support of family and their healthcare
providers. The patient should check blood
pressure and blood glucose daily, including
some post-prandial readings 1-2 hrs after a meal.
Medication, blood pressure, and glucose logs
are an indispensible part of safe and optimal
care (see Appendix 1 for examples). Having the
patient record weekly waist circumference and
body weight measurements may also be helpful
in monitoring progress. A dietitian trained in
carbohydrate reduction can assist patients with
identifying and overcoming barriers to adhering
to this intervention, including limited financial
or time resources, “trigger foods,” food addiction,
and eating out. Outpatient follow-up is essential
until new medication regimen is optimized.
Medication titration may need to occur multiple
times as insulin resistance improves. If a member
of the hospital healthcare team is not the primary
care provider, contact the primary care provider
and let them know of the dietary intervention
and accompanying medication changes. For
Jefferson Medical Center, an outpatient clinic
at WVU Center for Diabetes and Metabolic
Health often assists after hospital discharge.
Return visits allow additional opportunities
for education and encouragement. Laboratory
workup should be completed about 3 months of
initiating the dietary intervention. This should
include a complete metabolic panel and HbA1c;
waiting at least 6 months to repeat lipid panel
is advised. The primary care physician should
continue to check HbA1c every 3 months,
adjusting medications as necessary. Clinicians
should be cautious in discontinuing long-acting
insulin in anyone with possible irreversible beta
cell dysfunction due to autoimmunity, injury,
or beta cell failure of long-standing T2DM.
Most patients will notice a dramatic decline
in triglycerides (TG), increase in high-density
lipoprotein (HDL) cholesterol, and decrease
in HbA1c. Although some patients will also
show an increase in low-density lipoprotein
(LDL) cholesterol, a recent meta-analysis of
low-carbohydrate diets and lipid effects shows
an overall favorable response, concluding that,
“Large randomized controlled trials of at least 6
months duration with carbohydrate restriction appear superior in improving lipid markers when
compared with low-fat diets. Dietary guidelines
should consider carbohydrate restriction as an
alternative dietary strategy for the prevention/
management of dyslipidemia for populations
with cardiometabolic risk” [39]. The role of
LDL cholesterol alone as a risk predictor in
cardiovascular disease is tenuous [37], therefore
the patient’s atherosclerotic cardiovascular disease
(ASCVD) risk should be recalculated with the
new laboratory markers including TG and HDL
cholesterol. In almost all cases the patient can
be reassured of their risk profile if slight LDL
cholesterol elevation. Larger elevations of LDL
cholesterol, if they occur, would require an
individualized treatment plan.

Case study

DT is a 41-year-old African-American law
enforcement officer with a recent diagnosis of
T2DM when he presented to Jefferson Medical
Center in June 2017 with a glucose of 700,
HbA1c of 14.9, and serum creatinine of 7.
Other significant medical history included
hypertension, gout, hypercholesterolemia,
and obesity. His diabetic pharmacotherapy at
the time of admission was long-acting insulin
degludic injection (15 units daily), metformin
(1 g twice daily), lisinopril (40 mg daily),
metoprolol/hydrochlorothiazide (50 mg/12.5
mg daily), and simvastatin (40 mg daily). With
intensive hospital management of hydration and
insulin, renal failure improved, and he avoided
hemodialysis. Due to extreme insulin resistance
he was discharged on 70 units of insulin glargine
twice a day and short-acting insulin lispro, up
to 20 units before meals. Following the protocol
outlined above, he was introduced to the option
of low-carbohydrate eating. He was interested
in pursuing this option and arranged for quick
follow-up after discharge. Two weeks after
discharge, his creatinine was down to 1.16 and
glucose normalized on 20 units of long-acting
insulin a day. DT continued to follow a lowcarbohydrate,
sugar-free diet and was able to
stop insulin completely within a month after
discharge. On metformin alone, his HgA1c
results have been 6.7 at three months after
discharge, 5.8 at 13 months, and 5.9 at 17
months. He has been discharged from the renal
clinic, reduced close to 100 pounds of body
weight and several inches of waist, and returned
to his job and youth coaching. From near-dialysis
in June 2017, he has been able to maintain health
improvements for over 17 months and now has
the opportunity for a healthy future.

Discussion

Remission of prediabetes and T2DM has
not been fully defined or agreed upon in the
literature, as T2DM is most often treated as
a chronic progressive condition. However,
remission indicates the reversal or disappearance
of signs and symptoms, which can be temporary
or permanent, and this can be achieved in
T2DM with therapeutic levels of carbohydrate
reduction. Prediabetes may be considered to be
put in remission with a HbA1c measurement
of <5.7% and T2DM reversed with a HbA1c
measurement of <6.5% with or without the use
of an insulin-sensitizing agent such as metformin.
Remission can be defined as two measurements
below these thresholds at least two months apart,
again with or without the use of metformin [40].
Although the benefits of carbohydrate restriction
for individuals with T2DM are recognized, many
experts have raised concerns about whether
patients can adhere to such a diet indefinitely.
Because dietary carbohydrate is not an essential
nutrient [23], a well-formulated LCK diet that
includes a variety of vegetables presents no
health risks from nutritional deficits. However,
other considerations, such as traditional
or celebratory foods, should be taken into
account when discussing long-term adherence
to a low-carbohydrate dietary intervention. In
the context of selection of highly motivated
individuals or administration of programs that
encourage high adherence, remission of T2DM
is possible [22,41]. In term of sustainability of
this intervention, a recent survey of participants
voluntarily adhering to a low-carbohydrate diet
suggests that weight loss and diabetes remission
is sustainable when a low-carbohydrate diet
is incorporated as a lifestyle change [41]. The
survey found that before respondents started
a low-carbohydrate diet, nearly nine of 10
experienced intense hunger between meals. Once
on the diet, only 3.5% said they grew hungry
between meals. Respondents reported similar
improvements in other aspects of their physical
and psychological well-being. Of the 1,580
survey participants, more than half reported
staying on a low- carbohydrate diet for at least
one year, with 34% using this intervention
for more than two years. Further, those on the
diet for two years or more said that they had
largely maintained their weight loss. This is a
self-selected sample, with an obvious bias for
people who are experiencing success. However,
this data does show that long-term adherence is
possible. Whether or not and in what manner to allow additional dietary carbohydrate to the
diet will be an individual decision. It is unlikely
that a return to previous levels of carbohydrate
consumption would be recommended; to do so
would likely lead to a return of previous health
conditions that reduction of dietary carbohydrate
ameliorated. However, as with other dietary
components that are non-essential such as
alcohol, limited amounts may be tolerated. For
some individuals, increased dietary carbohydrate
may be offset by deliberating restricting calories
in a way that prevents weight gain. Other
individuals may prefer to forgo calorie counting
in favor of continued carbohydrate restriction.
For individuals with remission of T2DM, a reintroduction
of dietary carbohydrates requires
continued blood glucose monitoring and regular
HbA1c measurements.

Outpatient settings

Many patients eligible for low-carbohydrate
therapy and medication reduction present in
ambulatory settings. Although the protocol
described here was designed for use in an
inpatient setting, it may be adapted to an
outpatient setting. Patients on insulin therapy
may benefit significantly from a LCK dietary
intervention in either setting, but they present
significant challenges in medication management
given the time constraints of the outpatient
environment. In this case, consideration should
be made for inpatient initiation of a LCK
diet and medication management for poorly
controlled cases of T2DM, especially if severe
co-morbidities are already present. Otherwise,
patient education and community support from
physicians and allied healthcare providers is
especially important with regard to medication
management as dietary carbohydrate is reduced.
Ideally, as with the inpatient setting, a multidisciplinary
team of providers—including
clinicians, pharmacists, nurses, dietitians, and
health coaches—will collaborate on patient care.
Something as simple as cell phone technology
can greatly assist clinicians in the successful use of
this intervention. Daily text messaging between
the patients and the physician or another trained
team member allows medication reduction to
be safely tailored to the patient’s needs. In a
community setting, opportunities to meet and
socialize with others using low-carbohydrate
dietary interventions may assist with supporting
individuals in making dietary and behavior
changes. For example, at WVU Center for
Diabetes and Metabolic Health, where patients
from Jefferson Medical Center frequently receive follow-up care, the group-visit model is being
used to support patients and families in making
necessary lifestyle changes.

Additional considerations

This article has focused on the use of a LCK
dietary intervention to treat T2DM initiated
in a hospital setting; however, there are other
conditions for which this type of intervention
may be appropriate. Individuals with metabolic
syndrome (MetSyn) may also benefit from
dietary therapies that reduce carbohydrate.
Identify these individuals and placing them on
an individualized low-carbohydrate intervention
may help prevent progression of further metabolic
dysfunction and the development of T2DM or
other chronic diseases. Various definitions and
sets of identifying criteria for MetSyn have been
put forth [42]. The following conditions are
considered to be related features of metabolic
dysregulation. An individual presenting with 3
or more of these conditions can be identified as
having MetSyn:

• A large waistline (waist x2 > height). This also
is called abdominal obesity or “having an apple
shape.” Excess fat in the stomach area is a greater
risk factor for heart disease than excess fat in
other parts of the body, such as on the hips.

• High blood pressure (>130/85) or on medicine
to treat high blood pressure.

• High fasting blood sugar (>100 mg/dl) or on
medicine to treat high blood sugar.

Clinicians should note that the above criteria
may be inadequate in identifying MetSyn
in African-American populations. Elevated
triglycerides are closely associated with lower
HDL-cholesterol, which suggests a redundancy
in clinical criteria for MetSyn that is beyond
the scope of this paper, but which may exclude
from MetSyn diagnosis populations that do not
demonstrate this dyslipidemic profile [43-45].
A diagnosis of MetSyn, suspected from family
history of T2DM or other indications, may need
to be ascertained through more direct measures
of insulin resistance. Low-carbohydrate diets that
are restricted to ketogenic levels have been used
as therapeutic diets for epileptic seizures for a
number of years [46]. There is a robust literature on the implementation and effectiveness of
these diets. However, clinicians should note that
these diets are distinct from low-carbohydrate
diets used to treat T2DM in that they tend to
be far more restrictive and are directed at other
considerations, such as the generation of ketones
for therapeutic purposes, besides minimizing
blood glucose excursions and subsequent insulin
demands. Low-carbohydrate diets have also
been proposed as interventions for many other
health conditions, including obesity, polycystic
ovary syndrome (PCOS), gastroesophageal
reflux disease (GERD), non-alcoholic fatty liver
disease (NAFLD), and gout [35,47-50]. Many
of these have limited evidence secondary to little
research; however the principles of this guide
may be used for safe implementation of lowcarbohydrate
diet for other clinical presentations
as the research and clinical experience for using
this intervention for those conditions expands.

Conclusion

Low-carbohydrate diets are not a new
intervention for treatment of T2DM. A textbook
published in 1877 indicates that carbohydrate
reduction is the preferred treatment for patients
with diabetes: “There are few diseases which
present to the practitioner so clear an indication
of what is to be done...a Diabetic should exclude
all saccharine [sugary] and farinaceous [starchy]
materials from his diet” [51]. Leading endocrine
societies are now rediscovering this treatment.
The American Diabetes Association’s (ADA)
October 2018 joint position statement with the
European Association for the Study of Diabetes
(EASD) approved use of a low-carbohydrate diet
as Medical Nutrition Therapy (MNT) for adults
with T2DM [52]. The ADA’s recently released
Standards of Medical Care in Diabetes—2019
includes in its lifestyle management guidance
the use of low-carbohydrate diets as nutrition
therapy, reflecting the organization’s emphasizes
on a patient-centered, individualized approach
[53]. The ADA and the EASD both recognize
that LCK diets can be a safe, effective way for
people diagnosed with T2DM or prediabetes
to normalize HbA1c levels while lowering
medication therapy, reducing the risk of
hypoglycemia or other adverse medication
effects, and assisting in weight loss. In this
review, we highlight recent trials on the topic
but more importantly provide clinicians with
guidance for implementing this kind of dietary
intervention in their own hospitals or clinics.
In providing of a clinical protocol for using a LCK dietary intervention, this article offers the
foundations for a shared language for clinicians
to use in discussing and comparing interventions,
improving protocols, and managing shared
concerns. We do not expect this guidance
to provide a “one-size-fits-all” approach to
care; rather we expect that knowledge gained
from the clinical experiences of others will
inform a continued improvement in how lowcarbohydrate
dietary interventions are used
to treat patients. We do, however, anticipate a necessary change in how we discuss the course
and treatment of T2DM with patients. With a
simple, safe, effective dietary intervention, we
can change the conversation around T2DM
from one of progression to one of remission.

Funding

Laura Saslow’s time was supported, in part, by
the National Institute of Diabetes and Digestive
and Kidney Diseases (NIDDK, K01DK107456,
Saslow).